#79 F-2

SYNTHESIS: To a solution of 43.2 g KOH pellets in 250 boiling EtOH
there was added 96 g 4-methoxyphenol followed by the slow addition of
131.2 g allyl bromide, and the mixture was held under refluxing
conditions for 16 h. After cooling, the reaction was added to 1.6 L
H2O, and made strongly basic with 25% NaOH. This was extracted with
3x100 mL CH2Cl2, the extracts pooled, washed once with dilute NaOH and
then once with dilute HCl. Removal of the solvent under vacuum gave
93.8 g of 4-allyloxyanisole as a pale amber oil, which was used in the
following reaction without further purification.

A round-bottomed flask containing 93 g crude 4-allyloxyanisole was
equipped with an immersed thermometer and heated with an external
flame until an exothermic reaction set in at 230 °C. The temperature
rose to 270 °C and it was maintained there with the flame for five
minutes. After cooling to room temperature, the reaction mix was
poured into 2 L H2O and made strongly basic with the addition of 25%
NaOH. This dark aqueous phase was washed with 2x200 mL CH2Cl2, and
then acidified with HCl. This was then extracted with 2x200 mL
CH2Cl2, and the pooled extracts washed first with saturated NaHCO3 and
then with H2O. Removal of the solvent under vacuum gave 65.6 g of
2-allyl-4-methoxyphenol as a clear, amber oil. To a solution of 1.66
g of this crude phenol in 5 mL hexane with just enough CH2Cl2 added to
effect a clear solution, there was added 1.3 g phenylisocyanate
followed with three drops of triethylamine. An exothermic reaction
ensued which spontaneously deposited white crystals. These was
removed and hexane washed to give 2-allyl-4-methoxyphenyl N-phenyl
carbamate, with a mp of 88-89 °C. The acetate ester, from the phenol
and acetic anhydride in pyridine, did not crystallize.

To a half-hour pre-incubated mixture of 69 g POCl3 and 60 g
N-methylformanilide there was added 29.0 g
5-methoxy-2-methyl-2,3-dihydrobenzofuran and the mixture was heated on
the steam bath for 2 h. The reaction mixture was poured into 1 L H2O,
and allowed to stir overnight. The brown gummy solids were removed by
filtration, and air dried as completely as possible. These weighed 32
g and were shown by GC on OV-17 to consist of two benzaldehydeisomers
in a ratio of 7:2. This was triturated under 18 mL MeOH, and the
undissolved solids removed by filtration and washed with 6 mL
additional MeOH. The mother liquor and washings were saved. The 17.8
g of dull yellow solids that were obtained were repeatedly extracted
with 75 mL portions of boiling hexane (4 extracts were required) and
each extract, on cooling, deposited yellow crystals of the major
aldehyde. The dried crystals of
6-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran were combined (9.5
g) and had a mp of 80-82 °C. The methanol washes saved from above
were stripped of solvent, and the sticky, orange solids that remained
were enriched in the minor aldehydeisomer (3:2 ratio). Several
injections of this crude material into a preparative GC OV-17 column
gave sufficient quantities of the "wrong" isomer for NMR
characterization. The 2-methyl group was intact (eliminating the
possibility of a dihydrobenzopyranisomer) and the ring meta-proton
splitting required that the formyl group be in the benzofuran
7-position. This crystalline solid was, therefore,
7-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran.

EXTENSIONS AND COMMENTARY: This material, which is certainly a mixture
of two diastereoisomeric pairs of racemates since there are two chiral
centers present, showed no effects at levels of up to 15 milligrams
orally. Doses of 100 mg/Kg were without effects in mice following
i.p. injections, although half again this amount proved to be lethal.
In rats trained to discriminate LSD from saline, F-2 proved to be
about 40 times less potent than the reference compound DOM, requiring
some 5 mg/Kg for positive responses. But the human trials were only
up to about 0.2 mg/Kg.

This was the prototype compound that was originally put together to
justify giving a paper at a marijuana conference in Sweden, in 1968.
Although I had never done much with marijuana or with its principal
ingredients, I thought maybe I could bend the topic a bit to embrace
some potentially active phenethylamines. There is a story of an
international conference held in Geneva a few years earlier to discuss
the worrisome decrease in the elephant population. A German zoologist
invested a full eight-hour day in a summary of his 21 volume treatise
on the anatomy and the physiology of the elephant. A French
sociologist presented a lively slide show on the mating rituals and
rutting behavior of the elephant. And a rabbi from Tel Aviv entitled
his talk: "Elephants and the Jewish Problem." My Swedish talk should
have been named "Marijuana and the Psychedelic Amphetamines." The
memorable story of meeting the chief of the Swedish equivalent of the
Bureau of Narcotics, and ending up playing Mozart sonatas in the attic
of his home, has been spun out elsewhere in the book.

The original concept was a grand plan to imitate two of the three
rings of tetrahydrocannabinol. There is an aromatic ring (with an
alkyl group and two oxygens on it) and it is fused to a pyran ring
with a couple of methyl groups on it. So, if one were to tie the
methyl group at the 4-position of DOM around with a short carbon chain
into the oxygen atom at the five position, one could squint and say
that the resulting amphetamine was kinda something like an analogue of
THC. Thus, the resulting six-membered ring (a pyran) or five-membered
ring (a furan) could be peppered with methyl groups at different
locations (and up to two per location). If the ring was a
five-membered structure, then the parent system would be a benzofuran,
and the location of methyl groups on the ring would be indicated by
the appropriate numbers following the letter RFS which would stand for
"furan". And if it were to be a six-membered ring, the resulting
benzopyran would be indicated with a RPS for pyran, and again the
methyl group or groups would be indicated by the substitution
position. This code would cover all polymethylatedhomologues with
codes that would look like F-22 and P-2234. If any of them showed up
with fascinating activities, I would extend methyls to ethyls, and
work out some whole new naming code at some future time. An early
system, naming this compound 2-M for a methyl group on the 2-position
of the furan ring, was abandoned when it became apparent that the
pyran world would screw everything up.

The plain furan analogue, without any methyl groups on it, has been
made. Five-methoxybenzofuran formed the 6-formyl derivative (the
aldehyde) with a mp of 79-80 °C and from it the nitrostyrene (orange
needles, mp 89-91 °C) and the final amphetamine (white solids, as the
methanesulfonate, mp 141-144 °C) were prepared in a manner similar to
the preparation of F-2 above. In the rat studies, it was three times
more potent than F-2, but still some 15 times less potent than DOM.
And in initial human trials (of up to 30 milligrams) there were again
no effects noted. Naming of this material is easy chemically
(6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran) but tricky as to
code. If the numbers that follow the RFS give the location of the
methyl groups, then this material, without any such groups, can have
no numbers following, and should properly be simply "F." OK, it is
"F." The preparation or the attempted preparations of other homologues
such as F-23 and F-233 are outlined under the recipe for F-22.